The pain management market is segmented according to the severity of the pain being treated.                Mild pain (e.g. headache) is generally treated with over-the-counter drugs, such as aspirin.        Moderate pain (e.g. arthritis) is often treated with weak opioids such as codeine or hydrocodone that require a prescription, generally from a general practitioner.        Severe pain (e.g. cancer pain, chronic back pain) is treated with strong opioids such as morphine, oxycodone or fentanyl, which also require a prescription, often provided by a specialist.        
While opioids continue to remain the gold standard in pain relief, they have well 25 recognized shortcomings.                significant adverse side effects—e.g. respiratory depression, nausea, vomiting, dizziness, sedation, constipation;        tolerance—chronic sufferers often develop tolerance to opioids and require a stronger dose to achieve effective pain relief, concomitantly increasing the level of side effects;        dependency—concerns about addiction may influence clinicians to prescribe less than adequate doses; and        potential for abuse—recreational use.        
Tapentadol hydrochloride is an oral drug for the relief of moderate to severe acute pain. Tapentadol assumes a special position amongst centrally-acting analgesics, since this active ingredient gives rise to a pronounced inhibition of pain without the side effects which are known for opioids.
Currently available pharmacological treatment of pain includes the following analgesics: non-steroidal anti-inflammatory drugs (NSAIDs), cyclo-oxygenase II (COX-II) inhibitors, acetaminophen and opioids. Notwithstanding the numerous available analgesic medications, 60% to 80% of patients suffering from chronic pain are currently treated inadequately. Tapentadol helps fill the gap for those subjects whose pain cannot be effectively controlled by existing medications.
Tapentadol acts in two ways, opioid (narcotic) and non-opioid. It has a unique pharmacological profile with two postulated mechanisms of action, combining μ-opioid receptor agonism and norepinephrine reuptake inhibition in a single molecule. It is being developed in immediate-release and extended-release formulations.
The chemical structure of tapentadol (1) has been disclosed in EP-A-0693475 as compound (+21). The synthesis of tapentadol is described in Example 1 and Example 24 steps 1 to 3 and is outlined below (Scheme 1):

The synthetic precursor of tapentadol in the above scheme is (2R,3R)-3-(3-methoxy-phenyl)-N,N,2-trimethylpentanamine (7) which can be obtained by removing the tertiary hydroxy group of (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol (5) by consecutive conversion into the corresponding halogenide (6) with thionyl chloride and subsequent removal of the Cl by treatment with zinc borohydride, zinc cyanoborohydride and/or tin cyanoborohydride. This procedure has the disadvantage that the halogenide compound is prepared using an excess amount of thionyl chloride which is an aggressive chlorinating agent. Moreover the hydrogenation reagents such as zinc borohydride, zinc cyanoborohydride and tin cyanoborohydride present a considerable fire and health danger when used on an industrial scale. The main disadvantage, however, is the usage of column chiral chromatography for the separation of the stereoisomers.
WO 2004/108658 discloses an alternative process for obtaining (2R,3R)-3-(3-methoxy-phenyl)-N,N,2-trimethylpentanamine (1) by converting (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentenol (9) into a mixture of (2R,3R) (7) and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine (10) as outlined below (Scheme 2).

The resulting mixture of (2R,3R) and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethyl-pentanamine is then separated into its individual stereoisomers (7) and (10) in order to obtain the desired (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-amine (7), which can then be converted into tapentadol by e.g. heating with concentrated hydrobromic acid as described in EP-A-0693475.
WO 2005/000788 discloses an alternative process for obtaining (2R,3R)-3-(3-methoxy-phenyl)-N,N,2-trimethylpentanamine by converting (2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol into a mixture of (2R,3R) and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine as outlined below.

Both processes of WO 2004/108658 and WO 2005/000788 have the disadvantage that [3-(3-methoxyphenyl)-N,N,2-trimethylpentanamine is obtained as a mixture of the (2R,3R) and (2R,3S) stereoisomers which have to be separated in order to obtain the desired (2R,3R) stereoisomer. The undesired (2R,3S) stereoisomer cannot be converted into the desired (2R,3R) stereoisomer and has to be disposed of as chemical waste, which is economically undesirable for any industrial scale production.
WO 2008/012047 discloses yet another method for preparation of tapentadol, starting from 1-(3-methoxyphenyl)propan-1-one (Scheme 4):

WO 2008/012283 discloses the same preparation of tapentadol as WO 2008/012047, but with some modifications: the transformation of (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol into (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine was performed using trifluoroacetic anhydride instead of hydrogen chloride.
The main disadvantage of the above mentioned methods for the preparation of Tapentadol is the necessity of an enantioselective separation, using different chiral agents or chiral chromatography. Another disadvantage is the usage of Grignard reagents, which requires special equipment, extra dry solvents, inert atmosphere and other safety measures.
The above processes involve sophisticated reaction conditions and separation techniques which make them commercially less viable. Therefore, there is an unmet need for the development of a process for obtaining Tapentadol in an optically active pure form which is cost effective, uses easily available reagents, which is scalable with ease and is industrially feasible.